Project Summary Triple negative breast cancers (TNBCs) comprise only a subset of all breast cancers, yet they are highly aggressive and offer the worst prognosis. It is estimated that 40,000 American women will be affected by this disease in 2016. Recurrence rate is high after chemotherapeutic treatment, and to date no targeted therapies are available. There is thus an urgent need for new treatment options. Despite large-scale genome sequencing efforts, known breast cancer loci still explain only one- third of the cancer risk, thus limiting the identification of many high risk individuals. It is therefore imperative to identify additional breast cancer susceptibility genes and elucidate their mechanisms of action to develop comprehensive cancer risk assessment and targeted therapeutics. Our recent discovery that the DNA damage signaling protein BRCT-repeat inhibitor of hTERT expression (BRIT1) specifically interacts with TRF2 at telomeres in TNBCs is novel and provide new insights into mechanisms of how telomeres in these cells are protected from activating a DNA damage response. This knowledge will be highly valuable for the generation of new therapeutics against this deadly disease.